DESCRIPTION: The overall goals of this proposal are to investigate the pathophysiology of Type A (neuronopathic) and Type B (non-neuronopathic) forms of Niemann-Pick disease (NPD), and to develop and evaluate effective treatment for these disorders. The hematopoietic stem cell-based strategies for the treatment of Type B NPD will be evaluated, and the basic biology of acid sphingomyelinase (ASM) and its role in cell biology, mammalian development, and disease pathogenesis will be investigated. To facilitate these studies, full-length cDNAs encoding both human and murine ASM have been isolated and expressed. A knockout mouse model of NPD (ASMKO mouse) has been developed and characterized, and Chinese hamster ovary (CHO) cells stably overexpressing and secreting ASM have also been obtained. The specific aims of the research are toP: 1) transplant ASMKO mouse fetuses, newborn and adults will be transplanted with normal mouse bone marrow or fetal blood cells to assess the biochemical, pathological, and clinical correction of their non-neurologic phenotype; 2) transplant ASMKO mice with retrovirally-transduced bone marrow or fetal blood cells to compare the efficacy of the hematopoietic stem cell gene therapy (HSCGT) with that of transplantation alone; 3) investigate the biochemical and molecular basis for alternative ASM enzyme forms (lysosomal and secreted, Zn+2 activated) and evaluate their therapeutic usefulness (e.g., stability, uptake properties) of the recombinant enzyme forms purified from overexpressing CHO cells; 4) evaluate the use of a combined enzyme replacement/gene therapy protocol for the treatment of Type B NPD and compared the efficacy of treatment of Type B NPD with gene therapy alone; 5) investigate the development and tissue-specific expression of ASM in order to understand its role in ceramide-mediated signal transduction and mammalian development; and 6) continue investigating the pathophysiology of Types A and B NPD, the role of cholesterol in the pathogenesis of NPD will be studied. Finally, it will be determined whether NPD patients and ASMKO mice have defects in ceramide-mediated signal transduction. These animal model studies are expected to provide fundamental information on the pathophysiology of NPD and the role of ASM in mammalian development and disease pathogenesis.